PT  - JOURNAL ARTICLE
AU  - Rebecca S. Y. Wong
AU  - Veronique Bodart
AU  - Markus Metz
AU  - Jean Labrecque
AU  - Gary Bridger
AU  - Simon P. Fricker
TI  - Comparison of the Potential Multiple Binding Modes of Bicyclam, Monocylam, and Noncyclam Small-Molecule CXC Chemokine Receptor 4 Inhibitors
AID  - 10.1124/mol.108.049775
DP  - 2008 Dec 01
TA  - Molecular Pharmacology
PG  - 1485--1495
VI  - 74
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/74/6/1485.short
4100  - http://molpharm.aspetjournals.org/content/74/6/1485.full
SO  - Mol Pharmacol2008 Dec 01; 74
AB  - CXC chemokine receptor (CXCR)4 is an HIV coreceptor and a chemokine receptor that plays an important role in several physiological and pathological processes, including hematopoiesis, leukocyte homing and trafficking, metastasis, and angiogenesis. This receptor belongs to the class A family of G protein-coupled receptors and is a validated target for the development of a new class of antiretroviral therapeutics. This study compares the interactions of three structurally diverse small-molecule CXCR4 inhibitors with the receptor and is the first report of the molecular interactions of the nonmacrocyclic CXCR4 inhibitor (S)-N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydroquinolin-8-yl)butene-1,4-diamine (AMD11070). Fourteen CXCR4 single-site mutants representing amino acid residues that span the entire putative ligand binding pocket were used in this study. These mutants were used in binding studies to examine how each single-site mutation affected the ability of the inhibitors to compete with 125I-stromal-derived factor-1α binding. Our data suggest that these CXCR4 inhibitors bind to overlapping but not identical amino acid residues in the transmembrane regions of the receptor. In addition, our results identified amino acid residues that are involved in unique interactions with two of the CXCR4 inhibitors studied. These data suggest an extended binding pocket in the transmembrane regions close to the second extracellular loop of the receptor. Based on site-directed mutagenesis and molecular modeling, several potential binding modes were proposed for each inhibitor. These mechanistic studies might prove to be useful for the development of future generations of CXCR4 inhibitors with improved clinical pharmacology and safety profiles. The American Society for Pharmacology and Experimental Therapeutics